Focus on CME at the University of Université Manitoba Laval Two of a Kind? Treating both rhinitis & asthma By Jacques Hébert, MD In this article: 1. How are rhinitis and asthma linked? 2. Which treatments improve symptoms of both rhinitis and asthma? 3. What are the recent studies on upper and lower respiratory tract disease? Allergic rhinitis is a health problem that has been on the rise for several decades. 1,2 It is often associated with upper respiratory tract problems, particularly asthma. In the last few decades, rhinitis and asthma have, in fact, been considered unrelated conditions that were evaluated and treated independently by different professionals. As a consequence, both conditions have been generally undertreated. A number of recent observations allows for the re-evaluation of rhinitis and asthma as separate entities. 1,2 The notion of them as unique diseases of the respiratory tract with variable manifestations seems to have been instilled. These manifestations range from pure rhinitis, and rhinitis associated with bronchial hyperactivity, to full-blown asthma. The goal of this research is to gather evidence that supports the concept that allergosis, as a whole, consists of rhinitis and asthma. A good understanding of this reality will allow more precise diagnosis and better treatment of upper or lower respiratory tract disease. What are the links? Evidence of the links between rhinitis and asthma comes from several perspectives, namely epidemiology, embryology, anatomy, physiology, immunopathology, and therapy. A review of the immunopathologic and therapeutic evidence will illustrate the importance and logic of this concept. What is the immunopathologic evidence? The same cells are involved in both rhinitis and asthma (Table 1). Inflammatory cells carrying immunoglobulin E (IgE) receptors, derived from The Canadian Journal of CME / June 23 89
a common denominator from the bone marrow, seem to circulate from the systemic circulation to the respiratory tracts, where they are recruited by local inflammatory transmitters. Inflammatory cells are found in patients with allergic rhinitis and asthma. 3 The atopic immune response is identical for rhinitis and asthma. The IgE plays a dominant role; the same cytokins and inflammatory cells are found. 3-6 The concept of common pathophysiology is supported by studies dealing with specific nasal and pulmonary inducement tests. In fact, the Braunstalhl et al. group demonstrated that, after nasal provocation localized with an allergen (making sure there is no evidence of pulmonary contamination), both an objective and subjective nasal clinical response, as well as a pulmonary clinical response, can be observed. 7 Both nasal and pulmonary responses are accompanied by local inflammatory responses. Table 2 Meta-analyses for rhinitis and asthma Rhinitis: 16 studies: 759 patients Parameters: improvement of symptoms (nose/eyes); usage of emergency medication; at least 35 days without symptoms Odds ratio 1.81 (p <.5) Asthma: 54 studies Odds ratio (<1 prefer SIT) Increase in specific HRB.28 Increase in the use of medication.32 Increased symptoms.26 Increase in non-specific HRB.22 Impairment of pulmonary functions.56 Table 1 Cells involved in both rhinitis and asthma antigen-presenting cells including epithelial cells Langerhans or dendritic cells immunocompetent cells such as activated T lymphocytes and B lymphocytes cells involved in inflammation, including eosinophils, mast cells and neutrophils 12 1 8 6 4 2 Antigen Placebo Time h Time 25h Figure 1. Nasal inflammatory cells (eosinophils) after segmentary pulmonary provocation (mean +/- standard error). The same group also demonstrated the reverse correlation: a segmentary bronchial provocation resulted in significant pulmonary and nasal changes (Figure 1). 8 What is the therapeutic evidence? The only difference in the treatment of rhinitis and asthma lies in the adrenergic monitoring, where adrenergic agonists produce vasoconstric- Jacques Hébert is chief, allergy and clinical immunology, CHUQ, CHUL, clinical associate professor, Université Laval, and director, Allergy and Asthma Research Centre of Quebec, Quebec City, Quebec. 9 The Canadian Journal of CME / June 23
9 Nasal Symptoms: Score -9 6 3 Placebo Budesonide 7 14 21 28 35 42 49 Study day P<.5 (days 21-49) Figure 2. Treatment of patients with light asthma and seasonal allergic rhinitis with an inhaled steroid only (budesonide) and the effects on the clinical nasal response. Patients treated with inhaled steroids show significant clinical nasal improvements. CAPPING OFF OUR BIRTHDAY. (Anti-inflammatory analgesic agent with a mucosal protective agent) Arthrotec is contraindicated in pregnancy. Product Monograph available on request. Arthrotec is a registered trademark of G.D. Searle & Co., used under permission by Pharmacia Canada Inc.
Figure 3. Effects of specific immunotherapy on bronchial hyperactivity where A = before therapy when the patient is asymptomatic; B = when patient is symptomatic during the pollen season; and C = two years after therapy, during the pollen season. # of Patients 18 16 14 12 1 86 4 2 6 5 4 3 2 1 Winter 1998 Immunotherapy Summer 1998 Figure 4. Number of patients with or without asthma after three years of immunotherapy. The 151 patients did not have asthma at the beginning of the study. tion, and beta-adrenergic drugs induce pulmonary bronchodilatation. 9-11 The same drugs are used for both conditions for the same purpose. Furthermore, treatment of one condition favourably affects the other. Environmental control immunotherapy placebo Summer 2 No Asthma Asthma Odds ratio=2.52 Control Environmental control, which means eliminating allergenic factors which may contribute to the symptomatology from the environment, improves not only upper respiratory tract symptoms, but also lower respiratory tract symptoms. 12,13 Corticosteroids Locally administered nasal and pulmonary corticosteroids have been used widely as treatment in the last few decades, resulting in high efficacy without any side effects. 14 This approach has been totally effective in reducing morbidity due to both rhinitis and asthma. These results, however, may have also contributed to an unrealistic separation of the two diseases. We quickly noticed therapeutic effects that spread beyond the treatment application site. Administering intranasal steroids not only sharply reduced nasal symptoms, but also concurrently improved asthma and bronchial hyperactivity without directly filling the lungs, as demonstrated in radioisotopic studies. 15,16 Antihistamines Antihistamines that are very efficient in the treatment of allergic rhinitis are, in general, considered to be of little use and even dangerous to treat asthma, unless it is administered at very high doses (incurring side effects). However, several recent studies have shown that when standard therapeutic doses for allergic rhinitis are administered, there is also significant improvement in both light pulmonary symptoms and associated pulmonary functions. 17,18 Two retrospective studies involving more than 25, patients support the fact that adequate treatment of rhinitis improves asthma. 19,2 92 The Canadian Journal of CME / June 23
Topical Steroids It has also been proven that treatment of light asthma with a topical intrapulmonary steroid could not only improve pulmonary symptoms, but also improve clinical symptoms of allergic rhinitis (Figure 2). 21,22 Oral Drugs Several oral drugs have been administered over the years to treat both rhinitis and asthma. The impact of these drugs on the respiratory tract system has often been underestimated or disregarded. Theophylline has been used for decades to treat asthma, but is generally recognized to be of little efficacy in treating allergic rhinitis. Several studies have, however, suggested this treatment could also prevent allergic rhinitis. 23 It is also the case for new anti-phosphodiesterase drugs, such as roflumilast, which is efficient for asthma and chronic obstructive pulmonary disease, as well as for allergic rhinitis. 24,25 The same observation can be applied to antileukotriene drugs which improve asthma as well as rhinitis. As a result, the indication of antileukotrienes will also be approved for the treatment of rhinitis. 26 Specific Immunotherapy Take-home message Evidence supports the concept of global respiratory disease, with symptoms that range from the mouth and nasopharynx to the end of the alveoli. Rhinitis and asthma cannot be disassociated, both from a physiological and mechanistic perspective. One disease cannot be treated without treating the other. As rhinitis and asthma have been traditionally considered unrelated conditions, they have both been generally undertreated. Specific allergies are also treated with specific immunotherapy (SIT), or repeated allergen injections to improve the patients tolerance to them. This approach has definitely proven to be effective in several nasal studies. 27,28 Table 2 summarizes a meta-analysis of the efficacy of immunotherapy for the treatment of rhinitis. 29 SIT also significantly improves the associated pulmonary condition, regardless of the parameters studied. 27 Table 2 reports the results of a metaanalysis on the efficacy of the SIT in the treatment of asthma. 3 The SIT significantly improves the clinical parameters of asthma: specific and nonspecific hyperactivity; clinical symptoms of asthma; and pulmonary functions. The effects of SIT on bronchial hyperactivity are especially convincing in a recent study that measured off-season hyperactivity (Figure 3). During pollen season, patients had measurable hyperactivity which disappeared in those who were treated, but not in those who were not treated. 31 Figure 3 shows bronchial hyperactivity expressed in doses of metacholine (in mg), inducing a drop of forced expiratory volume in one second (FEV1) of 2% (PC2 [provocative concentration]). It was measured before any treatment, off-season, during allergy season, and after two years of treatment during pollen season. In this study, a certain degree of bronchial 94 The Canadian Journal of CME / June 23
hyperactivity is noted during pollen season in all patients, although the problem is corrected in patients who receive treatment (p<.1), which is significantly different than for patients who are not treated (p<.4). Immunotherapy is unequivocally efficient in controlling and treating lower respiratory symptoms. These symptoms are quite often the first things to improve after immunotherapy. Numerous studies have confirmed that SIT may also prevent the development of asthma. In a recent study, allergic patients without asthma were given immunotherapy or placebo, and observed for three years. In this study, the incidence of asthma in patients who were treated was significantly lower (Figure 4). 32 CME References 1. Bousquet J, Van Cauvenberge P, Khaltaev N: Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol 21; 18:(5 Suppl):S147-334. 2. Simons ER: Allergic rhinobronchitis: The asthma-allergic rhinitis link. J Allergy Clin Immunol 1999; 14(3 Pt 1):534-4. 3. Kay AB: Concepts of allergy and hypersensitivity. In: Kay AB (ed.): Allergy and Allergic Diseases. Oxford, UK, Blackwell Science Ltd., 1997, pp.23-35. 4. Gagnon R, Lian J, Boutin Y, et al: Seasonal enhancement of IL-4 induced IgE synthesis by peripheral blood mononuclear cells of atopic patients. Clin Exp Allergy 1993; 23(6):498-53. 5. Denburg JA, Inman MD, Sehmi R, et al: Hemopoietic mechanisms in allergic airway inflammation. Int Arch Allergy Immunol 1998; 117(3):155-9. 6. Bousquet J, Corrigan CJ, Venge P: Peripheral blood markers: evaluation of inflammation in asthma. Eur Respir J 1998;11:42-8s. 7. Braunstahl, GJ, Eoverbeek S, KleinJan A, et al: Nasal allergen provocation induces adhesion molecule expression and tissue eosinophilia in upper and lower airways. J Allergy Clin Immunol 21; 17(3):469-76. 8. Braunstahl GJ, Kleinjan A, Overbeek SE, et al: Segmental bronchial provocation induces nasal inflammation in allergic rhinitis patients. Am J Respir Crit Care Med 2; 161(6):251-7. 9. Boulet LP, Becker A, Bérubé D, et al: Canadian Asthma Consensus Report CMAJ 1999; 161(11 Suppl):S1-61. 1. Proceedings of the Canadian Rhinitis Symposium: Assessing and treating rhinitis. A practical guide for Canadian physicians. CMAJ 1994; 151(4 Suppl):1-27. 11. Hoffman BB, Lefkowitz RJ: Catecholamines, sympathomimetic drugs, and adrenergic receptor antagonists. In: Hardman JG, Limbird LE, Molinoff PB, et al (eds.): Goodman and Gilman s The Pharmacological Basis of HEADS UP. IT S OUR BIRTHDAY. (Anti-inflammatory analgesic agent with a mucosal protective agent) Arthrotec is contraindicated in pregnancy. Product Monograph available on request. Arthrotec is a registered trademark of G.D. Searle & Co., used under permission by Pharmacia Canada Inc.
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